U.S. patent number 5,236,932 [Application Number 07/793,924] was granted by the patent office on 1993-08-17 for method for treating parkinson's disease employing quinine.
This patent grant is currently assigned to E. R. Squibb & Sons, Inc.. Invention is credited to Susan A. Greenfield, Denyse Levesque.
United States Patent |
5,236,932 |
Greenfield , et al. |
August 17, 1993 |
Method for treating Parkinson's disease employing quinine
Abstract
A method is provided for treatment of Parkinson's disease or
controlling movement of a Parkinsonian patient by administering an
ATP-sensitive potassium channel blocker, such as a sulfonyl urea,
(for example, tolbutamide), or quinine.
Inventors: |
Greenfield; Susan A. (Oxford,
GB2), Levesque; Denyse (Chandler, CA) |
Assignee: |
E. R. Squibb & Sons, Inc.
(Princeton, NJ)
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Family
ID: |
27070676 |
Appl.
No.: |
07/793,924 |
Filed: |
November 18, 1991 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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554772 |
Jul 19, 1990 |
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Current U.S.
Class: |
514/305 |
Current CPC
Class: |
A61K
31/00 (20130101); A61K 31/64 (20130101); A61K
31/49 (20130101) |
Current International
Class: |
A61K
31/64 (20060101); A61K 31/00 (20060101); A61K
31/49 (20060101); A61K 031/44 () |
Field of
Search: |
;514/305,299 |
References Cited
[Referenced By]
U.S. Patent Documents
Other References
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Gates et al, J.A.M.A. 1960: 172:1351-1354. .
Gillhespy et al, Brit. Med. J. 1960: 2:1597. .
Noma A. (1983), "ATP-regulated K.sup.+ channels in cardiac muscle,"
Nature 305: 147-148. .
Kakei M. and Noma A. (1984) "Adenosine 5'-triphosphate-sensitive
single potassium channel in the atrioventricular node cell of the
rabbit heart," J. Physiol. 352: 265-284. .
Ashcrfot, F. M. et al (1984), "Glucose induced closure of single
potassium channels in isolated rat pancreatic .beta.-cells," Nature
312: 446-448. .
Sturgess, N. C. et al (1985), "The sulphonylurea receptor may be an
ATP-sensitive potassium channel," Lancent 8435: 474-475. .
Standen, N. B. et al (1989), "Hyperpolarizing vasodilators activate
ATP-sensitive K.sup.+ channels in arterial smooth muscle," Science
245: 177-180. .
Mourre, C. et al (9189), "Antidiabetic sulfonylureas: localization
of binding sites in the brain and effects on the hyperpolarization
induced by anoxia in hippocampal slices," Brain Res. 486: 159-164.
.
Virsolvyl-Vergine, A. et al (1988), "An endogenous ligand for the
central sulfonylurea receptor," FEBS Letters 242: 65-69. .
Ungerstedt, U. (1971), "Striatal dopamine release after amphetamine
or nerve degeneration revealed by rotational behaviour," Acta
Physiol. Scand. Suppl. 367: 49-68. .
Greenfield, S. A. et al (1984), "A noncholinergic function for
acetylcholinesterase in the substantia nigra:behavioural evidence,"
Expt. Brain Res. 54: 513-520..
|
Primary Examiner: Waddell; Frederick E.
Assistant Examiner: Hook; Gregory
Attorney, Agent or Firm: Rodney; Burton
Parent Case Text
This is a division of application Ser. No. 554,772, filed Jul. 19,
1990.
The present invention relates to a method for treating Parkinson's
disease or controlling movement of a Parkinsonian patient by
administering an ATP-sensitive potassium channel blocker.
Background of the Invention
A species of potassium channel that is dependent on adenosine
triphosphate (ATP) was first described in cardiac muscle by Noma A.
(1983), "ATP-regulated K+ channels in cardiac muscle,"Nature 305:
147-148. This channel has attracted increasing interest due to its
unusual and close association with cell metabolism. Ashcroft, F. M.
(1988), "Adenosine 5-triphosphate-sensitive potassium
channela,"Ann. Rev. Neurosci. 11: 97-118. It is now well
established that ATP-sensitive potassium channels are present in
diverse tissues i.e. cardiac muscle, (Kakei M. and Noma A. (1984)
"Adenosine 5'-triphosphate-sensitive single potassium channel in
the atrioventricular node cell of the rabbit heart," J. Physiol.
352: 265-284, Noma A. and Shibasake, T. (1985), "Membrane current
through adenosine-triphosphate-regulated potassium channels in
guinea-pig ventricular cells," J. Physiol. 363: 463-480),
pancreatic beta cells (Findlay, I., Dunne, M. J., and Petersen, O.
H. (1985a), "ATP-sensitive inward rectifier and voltage- and
calcium activated K.sup.+ channels in cultured pancreatic islet
cells," J. Memb. Biol. 88:165-172; Dunne, M. J., Findlay, I.,
Petersen, O. H. and Wollheim, C. B. (1986), "ATP-sensitive K.sup.+
channels in an insulin-secreting cell line are inhibited by
D-glyceraldehyde and activated by membrane permeabilization." J.
Memb. Biol. 93:271-279; Ashcroft, F. M. et al (1984), "Glucose
induces closure of single potassium channels in isolated rat
pancreatic .beta.-cells," Nature 312:446-448); skeletal muscle
(Sturgess, N. C., Ashford, M. L. J., Cook, D. L. and Hales, C. N.
(1985), "The sulphonylurea receptor may be an ATP-sensitive
potassium channel," Lancet 8435:474-475) and smooth muscle
(Standen, N. B., Quayle, J. M., Davies, N. W., Brayden, J. E.,
Huang, Y. and Nelson, M. T. (1989), "Hyperpolarizing vasodilators
activate ATP-sensitive K.sup.+ channels in arterial smooth muscle,"
Science 245:177-180). More recently, indirect evidence has
suggested that the ATP-sensitive channel may also be present in the
brain: sulfonylureas, which are potent blocking agents of this
channel in heart and beta cells, display selective binding in
certain brain regions (Mourre, C., Ben Ari, Y., Bernardi, H.,
Fosset, M. and Lazdunski, M. (1989 ), "Antidiabetic sulfonylureas:
localization of binding sites in the brain and effects on the
hyperpolarization induced by anoxia in hippocampal slices," Brain
Res. 486:159-164) and indeed an endogenous ligand for a central
sulfonylurea receptor has been described (Virsolvy-Vergine, A.,
Bruck, M., Dufour, M., Cauvin, A., Lupo, B. and Bataille, D.
(1988), "An endogenous ligand for the central sulfonylurea
receptor," FEBS Letters 242 65-69). It has also been found that
sulfonylurea binding sites appear to be highest in regions of the
brain associated with the control of movement, i.e. motor cortex,
cerebellar cortex, globus pallidus and substantia nigra (Mourre et
al., supra, 1989).
It is well known that disparities in the availability of dopamine
(DA) between the two nigrostriatal systems leads to circling
behaviour in a direction towards the side of dopamine deficiency
(Ungerstedt, U. (1971), "Striatal dopamine release after
amphetamine or nerve degeneration revealed by rotational
behaviour," Acta Physiol, Scand. Suppl.367:49-68). This model has
previously proved valuable in assessing the action of putative
neuroactive agents, i.e. substances introduced locally into the
substantia nigra can initiate circling behaviour in otherwise
normal rats (Greenfield, S. A., Chubb, I. W., Grunewald, R. A.,
Henderson, Z., May J., Portnoy, S., Weston J. and Wright, M. D.
(1984), "A non-cholinergic function for acetylcholinesterase in the
substantia nigra:behavioural evidence," Expt. Brain Res.
54:513-520).
DESCRIPTION OF THE INVENTION
In Parkinson's disease, a portion of the neurons in the brain which
is important in the regulation of movement has been found to
degenerate. This portion of the neurons contains a pore or channel
in the membrane that lets potassium out of the cell, under certain
conditions relating to the metabolism in the neuron ("K-ATP
channel"). In accordance with the present invention, by
administering to the brain of a Parkinsonian patient, especially
the substantia nigra portion, thereof, a substance which blocks the
K-ATP channel, otherwise uncontrollable movements of the patients
may be controlled.
In accordance with the present invention, a method is provided for
treating Parkinson's disease wherein a therapeutically effective
amount of a pharmaceutical which blocks an ATP-sensitive potassium
channel in the brain is administered to a mammalian species in need
of such treatment.
In addition, in accordance with the present invention, a method is
provided for controlling movement of a Parkinsonian patient,
wherein a therapeutically effective amount of a pharmaceutical
which blocks the ATP-sensitive potassium channel in the substantial
nigra is administered to modify the net activity of the
nigrostriatal pathway to control movement.
The pharmaceutical employed in the methods of the present invention
will be an effective blocker of the ATP-sensitive potassium channel
in the brain. Examples of such a pharmaceutical include, but are
not limited to sulfonyl ureas such as glyburide
(1-[[p-[2-(5-chloro-O-anisamido)ethyl]phenyl]sulfonyl]-3-cyclohexylurea);
chloropropamide(1-[(p-chlorophenyl)sulfonyl]-3-propylurea);
glipizide(1-cyclohexyl-3-[[p-[2-(5-methyl-pyrazinecarboximido)ethyl]phenyl
]sulfonyl]urea);
tolazamide-(benzenesulfonamide-N-[[(hexahydro-1H-azepin-1-yl)amino]-carbon
yl,-4-methyl), or tolbutamide (benzene-sulfoamide,N-(butylamino)
carbonyl]-4-methyl), with the latter being preferred. In addition,
quinine may also be employed in place of the sulfonyl urea.
Although the K-ATP channel blocker employed in the methods of the
invention may be administered systemically, such as orally or
parenterally, it is preferred that the K-ATP channel blocker be
administered locally, for example, by carotid injection, lumbar
puncture or cisternal puncture. The K-ATP blocker will be
administered for as long as a treatment for Parkinson's disease or
control of movement in Parkinsonian patients is required.
With regard to dosage of K-ATP channel blocker, where a wide region
of the brain is to be treated, for example, by intracarotid
injection, lumbar puncture or cisternal puncture, from about 0.1 to
about 20 mg/kg/treatment and preferably from about 0.5 to about 15
mg/kg/treatment will be employed, depending upon the particular
K-ATP channel blocker employed.
Where the K-ATP channel blocker is to be administered sytemically,
such as orally or parenterally, it will be administered in an
amount to achieve a steady state level of K-ATP channel blocker in
the blood. Thus, for systemic treatment, the K-ATP channel blocker
may be administered in an amount within the range of from about 0.5
to about 20 mg/kg for each treatment and preferably from about 1 to
about 15 mg/kg for each treatment.
In carrying out the method of the present invention, the K-ATP
channel blocker may be administered to mammalian species, such as
monkeys, dogs, cats, rats, and humans. The K-ATP channel blocker
may be incorporated in a conventional systemic dosage form, such as
a tablet, capsule, elixir or injectable. The above dosage forms
will also include the necessary carrier material, excipient,
lubricant, buffer, antibacterial, bulking agent (such as mannitol),
anti-oxidants (ascorbic acid of sodium bisulfite) or the like.
Claims
What is claimed is:
1. A method for controlling movement of a Parkinsonian patient,
which comprises administering to a parkinsonian patient in need of
treatment, an anti-Parkinson's disease effective amount of quinine
which blocks the ATP-sensitive potassium channel in the substantia
nigra to modify the net activity of the nigrostriatal pathway to
control movement.
2. The method as defined in claim 1, wherein the pharmaceutical is
administered to the substantia nigra of the brain.
3. The method as defined in claim 1 wherein quinine is administered
by infusion into the substantia nigra and blocks the ATP-sensitive
potassium channel.
4. The method as defined in claim 1 wherein the pharmaceutical is
administered locally in an amount of from about 0.1 to about 20
mg/kg/treatment.
5. The method as defined in claim 1 wherein the pharmaceutical is
administered by infusion into the substantia nigra and blocks the
ATP-sensitive potassium channel.
6. The method as defined in claim 1 wherein the pharmaceutical is
administered into the pars compacta or pars reticulata.
7. The method as defined in claim 1 wherein the pharmaceutical is
administered systemically or locally.
8. The method as defined in claim 1 wherein the pharmaceutical is
administered locally by injection in the carotid artery, or by
lumbar puncture or cisternal puncture.
Description
BRIEF DESCRIPTION OF THE FIGURES
FIG. 1 is a graph which shows the effects of tetraethylammonium on
circling behavior in the rat, as described in Example 5;
FIG. 2 shows the effects on circling behavior of tolbutamide
infused into a) the pars compacta and, b) the pars reticulata, as
described in Example 5; and
FIG. 3 shows the effects of quinine on circling behavior, as
described in Example 5.
The following Examples represent preferred embodiments of the
present invention.
EXAMPLE 1
An injectable solution for use in administering tolbutamide by
injection in the carotid artery or by lumbar puncture for treating
Parkinson's disease is produced as follows:
______________________________________ Tolbutamide 250 mg Sodium
chloride 25 mg Polyethylene glycol 400 1.5 l Water for injection
qs. 5.1 l. ______________________________________
The tolbutamide and sodium chloride are dissolved in 1.5 liters of
polyethylene glycol 400 and 3 liters of water for injection and
then the volume is brought up to 6.5 liters. The solution is
filtered through a sterile filter and aseptically filled into
presterilized vials which are then closed with presterilized rubber
closures. Each vial contains 25 ml of solution in a concentration
of 50 mg of active ingredient per ml of solution for injection.
EXAMPLE 2
An injectable for use in treating Parkinson's disease is prepared
as described in Example 1 except that quinine is employed in place
of tolbutamide.
EXAMPLE 3 AND 4
An injectable for use in treating Parkinson's disease is prepared
as described in Example 1 except that glyburide or glipizide is
employed in place of tolbutamide.
EXAMPLE 5
Recent evidence suggests that an ATP-sensitive potassium channel is
present in the brain. From ligand binding studies it has been
inferred that this relatively unfamiliar channel is particulary
densely distributed in areas associated with motor control. The
purpose of this study was thus to examine whether pharmacological
agents specific for the ATP-sensitive channel in other tissues had
effects on a particular motor behaviour associated with the
substantia nigra: the effects of microinfusion into the substantia
nigra of diverse potassium channel blocking agents were examined on
initiation of circling behaviour in the normal rat.
The effects of microinfusion into the substantia nigra of
substances known to block the ATP-sensitive potassium channel i.e.
the sulfonylurea tolbutamide and quinine (Ashcroft, supra, 1988)
were examined on the motor behaviour of the freely moving rat.
These effects were compared with those of a classic general
blocking agent of most potassium channels, which is nonetheless not
very efficacious at inhibiting the ATP-sensitive potassium channel
i.e. tetraethylammonium chloride (TEA) (Findlay et al., 1985b).
MATERIALS AND METHODS
Animal Preparation
Guide cannulae (Plastic Products Co) were implanted unilaterally in
the region of the substantia nigra of surgically anaesthetized 250
g male Wistar rats (AP: -5.0; L: -2.2; DV: -7.0; skull levelled
between bregma and lambda; Paxinos and Watson. The animals were
then left for twenty-four hours to allow full recovery from
surgery.
Infusion Procedure
In order to infuse solutions, a dummy cannula was replaced by an
internal cannula (Plastic Products Co) within the implanted guide
cannula such that it protruded 0.5 mm approximately. Solutions were
infused through the internal cannula connected to a 10 .mu.l
Hamilton syringe by inert capillary tubing (0.010"I.D.) and driven
by an automatic pump at a rate of 1.mu.l/1O min. After 10 min the
pump was switched off but the internal cannula left in place for a
subsequent minute. During infusion rats were freely-moving in a
restricted area.
ASSESSMENT OF CIRCLING BEHAVIOUR (i) Test for circling prior to
drug infusion:
Before implantation of the guide cannula, all rats were tested for
any inherent bias: 10 min following administration of d-amphetamine
sulphate (5mg/kg i.p.) they were placed in a circular bowl (12
inches dia.) and the net number of 360.degree. turns/min noted for
20 min. Animals with a mean score of 2 turns/min or more were not
used further. The remaining rats were then implanted with an outer
cannula in one substantia nigra. After full recovery from surgery,
the rats were placed on two occasions in the bowl to habituate them
to the environment. Following that they were tested for circling as
described above to ascertain whether the implant itself caused a
bias in direction of movement. Again animals with a mean score of 2
turns/min or more were not used further. (ii) Test for circling
behaviour post-drug infusion: All rats were given two
microinfusions, one of drug and one of vehicle solution: however
half received drugs before control infusion whilst the remainder
were given the vehicle first. Hence any artefactual effect
resulting from mechanical stimulation or tissue scarring could be
identified. Infusions were performed over ten minutes and were
followed immediately by administration of amphetamine: rotation was
observed ten minutes after this procedure for the subsequent twenty
minutes. In order to ascertain whether the infusions had any
lasting effects, all rats were again challenged with amphetamine
the following day and tests for rotation performed as described
above. When the rats displayed the preinfusion circling score, the
two groups were interchanged, i.e. animals previously given drug
received control and vice-versa and the subsequent procedure was
repeated as outlined above.
Drug Solutions
All drugs were infused in a volume of 1 .mu.l. Quinine
hydrochloride (Sigma, 1.times.10.sup.-4 M), and tetraethylammonium
chloride (TEA) (Sigma, 1.times.10.sup.-2 M) were administered in a
vehicle of NaCl (0.9% w/v). For tolbutamide (Sigma,
2.5.times.10.sup.-4 M), there was used NaCl (0.9% w/v) plus DMSO
(Sigma, 0.5M stock solution) so that the powder would dissolve more
readily.
Histological Procedures
At the end of the experiment, the animals were deeply anaesthetised
and perfused with formaldehyde. The brains were removed and placed
in formaldehyde and sucrose for at least twenty-four hours prior to
sectioning. Cannulae placement within the substantia nigra were
verified by examination of (50 .mu.m) frozen cut sections, stained
with cresyl violet. Placements were classified `blind` by an
outside observer as in pars compacta or pars reticulata. Any cases
where the cannulae were aberrantly placed were discarded.
Reasons for Elimination of Data
In addition to those mentioned above, approximately twenty further
rats were discarded from the study, for the following reasons: ill
health post surgery, intra-cerebral haemmoragh, blockage in
infusion pump or guide cannula. Furthermore it was occasionally
observed that some rats did not display circling behaviour, even
though there was no obvious reason (as above).
Analysis
Values were calculated in each group by averaging the mean scores
(.+-.SEM) of net number of 360.degree. turns/min from each animal
FIGS. 1, 2, and 3. The effect of each drug on circling behaviour
(stage C) was compared with the effect of control infusion (stage
B). Statistical significance was measured using a paired Student's
t-test.
RESULTS
Administration of TEA had no effect on the motor behaviour of a
total of 8 rats (0.04.+-.0.1 turns/min., NaCl infusion: 0.07.+-.0.1
turns/min TEA infusion), FIG. 1 shows the effects of TEA on
circling behaviour. Histogram shows the mean (.+-.SEM) for four
experimental stages in 8 rats in the presence of
amphetamine-challenge:
(A) 3 days post implant of outer cannula
(B) Immediately following infusion of NaCl vehicle
(C) Following infusion of TEA Cl.
(D) Twenty four hours following (C), i.e. TEA infusion.
By contrast, infusion of tolbutamide induced marked circling
behaviour `ipsiversley` or `contraversively` i.e. either towards
(1.8.+-.0.4 turns/min) or away from (1.2.+-.0.6 turns/min) the
treated side (FIG. 2). FIG. 2 shows the effects on circling
behaviour of tolbutamide infused into (a) the pars compacta for 6
rats and (b) the pars reticulata for 5 rats. In each case
Histograms show circling scores for experimental stages as in
legend to Fig, 1; stage C denotes immediate effects of tolbutamide.
Note when drug is infused into pars compacts (a), rotation is
towards the implanted side and is significant with respect to
control values at the level p<0.01. When the drug is infused
into the pars reticulata, turning occurs in the opposite direction
to (a) i.e. away from the treated side; significant with respect to
control values: p<0.05. Subsequent histological examination
showed that the direction of circling corresponded to the placement
of the cannulae within the substantia nigra: rats with injection
cannulae implanted in the pars compacta all circled towards the
treated side whereas those rotating away from the side of infusion
were implanted with cannulae in the pars reticulata, (FIG. 2).
Following application of quinine, a total of 6 rats with cannulae
implanted either in the pars compacta or pars reticulata displayed
drug-induced circling towards the site of infusion (1.11.+-.0.47
turns/min) significant with respect to control values: p<0.01
(FIG. 3).
Following infusion of either quinine or tolbutamide, motor
behaviour reverted to preinjection values within twenty-four hours
(FIGS. 2 and 3).
The Ionic Basis of Drug-Induced Rotation
Unlike tolbutamide, application of tetraethylammonium chloride
(TEA) in either the SNc or the SNr did not modify circling
behaviour. TEA is known to block a wide range of potassium channels
(Latorre, R. and Miller, C. (1983), J. Membrane Biol. 71:11-30).
Indeed, in the concentration used in this study, TEA inhibits the
voltage-activated potassium channels responsible for action
potential repolarization in pars compacta cells (Llinas, R.,
Greenfield, S. A. and Jahnsen, H. (1984), "Electrophysiology of
pars compacta cells in the in vitro substantia nigra- a possible
mechanism for dendritic release," Brain Res. 294:127-132.
Nedergaard, S., Bolam, J. P. and Greenfield, S. A. (1988),
"Facilitation of dendritic calcium conductance by
5-hydroxytryptamine in the substantia nigra," Nature 333:174-177;
Harris, N. C., Webb, C. and Greenfield, S. A. (1989), "A possible
pacemaker mechanism in pars compacta neurons of the guinea pig
substantia nigra revealed by various iopn channel blocking agents,"
Neuroscience 37:355-362). It would seem then that blockade of
voltage-gated potassium channels in general could not account for
the circling behaviour seen.
On the other hand, TEA is not a very effective blocker of the
ATP-sensitive potassium channel, (Findlay, et al., supra, 1985b).
Furthermore, sulfonylureas such as tolbutamide, are effective and
selective blockers of this channel (Schmid-Antomarchi, H., De
Weille, J. R., Fosset, M. and Lazdunski, M. (1987), "The receptor
for antidiabetic sulfonylureas controls the activity of the
ATP-modulated K channel in insulin-secreting cells," J. Biol. Chem.
262: 15840-15844; Sturgess et al., supra, 1985). Since two
chemically unrelated substances which caused similar and specific
behavioural effects have in common the property of blocking
ATP-sensitive potassium channels, the most parsimonious explanation
of the drug-induced circling seen is that the ATP-sensitive
potassium channel may selectively underlie a neuronal mechanism in
the substantia nigra involved in the control of movement.
Specificity of Pars Compacta and Pars Reticulata
It is particularly noteworthy that application of tolbutamide
resulted in circling behaviour in a direction dependent on whether
the infusion was either in the pars compacta or pars reticulata. A
comparable duality of behavioural response has already been
reported following application of GABA to the two main
sub-divisions of the substantia nigra (Coward, D. M. (1982),
"Nigral actions of GABA agonists are enhanced by chronic
fluphenazine and differentiated by concomittant flurazepam,"
Psychopharm. 76:294-298). Furthermore, it has been demonstrated
that pars compacta and pars reticulata neurons can be respectively
inhibited and excited by the same substance, in this case dopamine
(Waszczak, B. I. et al. (1983),"Dopamine modulation of the effects
of aminobutyric acid on substantia nigra pars reticulata neurons,"
Science 220:218-221). It might similarly be the case therefore that
tolbutamide is having differential effects on pars compacta and
pars reticulata cells. These effects could influence output
pathways in two, not mutually exclusive ways: direct relays to the
respective targets of compacta and reticulata cells, and/or
indirect modification of pars compacta cell output via recurrent
collaterals of pars reticulata cells affected by the drug, as
already postulated for the GABA-induced excitation of pars compacta
cells (Grace, A. A. and Bunney, B. S. (1979)," Paradoxical GABA
excitation of nigral dopaminergic cells: indirect mediation through
reticulata inhibitory neurons," Eur. J. Pharm. 59:211-218). On the
other hand, it is worth bearing in mind that long `apical`dendrites
extend in a dorso-ventral plane from nigrostriatal cell somata in
the pars compacta into and throughout the pars reticulata (Juraska,
J. M., Wilson, C. J. and Groves, P. M. (1977),"The substantia nigra
of the rat: a Golgi study," J. (Comp. Neurol. 172:585-600. Wassef,
M., Berod, A. and Sotelo, C. (1981), "Dopaminergic dendrites in the
pars reticulata of the rat substantia nigra and their striatal
input. Combined immunocytochemistry localisation of tyrosine
hydroxylase and anterograde degeneration." Neuroscience
6:2125-2139; Greenfield, S. A. (1985), "The significance of
dendritic release of transmitter and protein in the substantia
nigra," Neurochem Int. 7:887-901). Hence injections into the pars
reticulata might principally entail local application of drug to
pars compacta cell dendrites: the differences observed between
injections in the two regions might be caused by different
responses elicited from drug application to different parts of the
same cell type. It appears that the membrane properties of the
apical dendrites are different from those of the cell body in the
pars compacta (see Nedergaard et al. supra, 1988)
Significance of ATP-sensitive Potassium Channel in Circling
Behaviour
According to the model of Ungerstedt, supra (1971), contraversive
circling implies that there is a relatively greater amount of
available dopamine in the striatum of the treated side. Hence, the
results suggest that injection of tolbutamide in the pars
reticulata has the net effect of enhancing the excitability of the
nigrostriatal pathway, whereas in the pars compacta quinine, and
tolbutamide have caused a net decrease in striatal release of
dopamine. It is surprising that a drug such as tolbutamide, which
should depolarize the cell by blocking potassium efflux, appears to
be an inhibitory agent. However, pars compacta cells have been
shown to generate a calcium-mediated conductance that facilitates
burst firing but which is deinactivated only at hyperpolarised
potentials (Kita, T., Kita, H. and Kitai, S. (1986),"Electrical
membrane properties of rat substantia nigra compacta neurons in an
in vitro slice preparation." Brain Res. 372:21-30). It would follow
then that in these pars compacta cells, blockade of
hyperpolarisation would have the paradoxical effect of a net
inhibition.
SUMMARY
Application of tolbutamide and quinine, but not tetraethylammonium,
caused circling behaviour. However, in the case of tolbutamide
application, the direction of circling was dependent on whether the
site of infusion was in the pars compacta or pars reticulata. On
the other hand, the effects of quinine were the same, irrespective
of site of application within the substantia nigra, that is, in the
same direction as seen following injection of tolbutamide into the
pars compacta. Quinine and tolbutamide are different chemical
species which both, unlike tetraethylammonium, principally block
the ATP-sensitive potassium channel. It therefore seems that an
ATP-sensitive potassium channel in nigra cells could play a
selective role in modifying the net activity of the nigrostriatal
pathway, and hence the control of movement.
* * * * *